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KR-20260064460-A - NOVEL COMPOUNDS HAVING INHIBITORY ACTIVITY AGAINST LEUKEMIA CELL LINES AND MEDICAL USE THEREOF

KR20260064460AKR 20260064460 AKR20260064460 AKR 20260064460AKR-20260064460-A

Abstract

The present invention relates to a novel compound having inhibitory activity against leukemia cell lines and its medical use. The novel compound according to the present invention has excellent inhibitory activity against leukemia cell lines and can treat related diseases, and in particular has an excellent therapeutic effect on acute myeloid leukemia (AML), so it can be effectively utilized in the treatment of leukemia as described above.

Inventors

  • 이원태
  • 송지준
  • 김나연
  • 진정욱
  • 권수경
  • 김수희
  • 황준연

Assignees

  • 에피노젠 주식회사
  • 재단법인 대구경북첨단의료산업진흥재단

Dates

Publication Date
20260507
Application Date
20250521
Priority Date
20241030

Claims (8)

  1. A compound represented by the following chemical formula 1 or a compound selected from pharmaceutically acceptable salts thereof: <Chemical Formula 1> In the above chemical formula 1, R1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, or amino, and R2 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, or (C1-C4)alkoxy, and R 3 is or Selected from, Here, R 3' is hydrogen or (C1-C4)alkyl, and X is oxygen or sulfur.
  2. In Article 1, In the above chemical formula 1, R1 is selected from (C1-C2)alkyl, trifluoromethyl, or amino, and R2 is selected from hydrogen, halogen, (C1-C2)alkyl, trifluoromethyl, or (C1-C2)alkoxy, and R 3' is hydrogen or (C1-C2)alkyl.
  3. In Article 1, The above compound is, Compound characterized by comprising the following compounds: 3-(4-thioureidobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromail)sulfonyl)-phenyl)benzamido (compound 1), 3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 2), 4-methyl-3-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 3), 4-methyl-3-(3-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido (compound 4), 4-methyl-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 5), 3-Thioureido-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (compound 6), 4-methyl-3-(3-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 7), 3-(3-methylureido)-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (compound 8), 3-(3-methylureido)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (compound 9), 3-Thioureido-N-(3-((4-((trifluoromethyl)celponyl)phenyl)carbamoyl)phenyl)benzamide (compound 10), 4-fluoro-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 11), 3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 12), 3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 13), 4-methyl-3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 14), 4-methyl-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 15), 3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 16), 4-methyl-3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 17), 4-methyl-3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 18), 3-(4-(3-methylthiouredo)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 19), N-(3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-ureidobenzamido)benzamide (compound 20), 4-fluoro-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 21), 2-fluoro-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 23), 2-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 24), N-(3-(methylsulfonyl)phenyl)-3-(3-thioureidobenzamido)benzamide (compound 25), N-(3-(methylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide (compound 26), 3-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 29), 3-methyl-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 30), 3-(4-(3-methylthiouredo)benzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 31), N-(3-sulfamoylphenyl)-3-(4-thioureidobenzamido)benzamide (compound 32), N-(3-(ethylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide (compound 33), 3-Guanidino-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 34), 3-(3-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 35), 3-(3-carbamothioilbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 36), 3-Carbamothioil-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 37), 3-Carbamothioil-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 38), 3-(4-carbamothioilbenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 39), 3-(4-carbamothioilbenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 40), 3-(4-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 41), 3-(4-carbamothioilbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 42), 3-(3-carbamothioilbenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 43), 3-(3-carbamothioilbenzamido)-4-methoxy-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 44), 3-(3-carbamothioilbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 45), 3-(3-carbamothioilbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 46), 3-(4-carbamothioilbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 47) 3-(4-carbamothioilbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 48), 5-(3-carbamothioilbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 49), 5-(4-carbamothioilbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 50), 3-(4-carbamothioilbenzamido)-N-(3-(ethylsulfonyl)phenyl)benzamide (compound 51), 5-(4-carbamothioilbenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 52), 3-(4-carbamothioilbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 53), 3-(3-carbamothioilbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 54) and 3-Carbamothioil-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 55).
  4. A pharmaceutical composition for the prevention or treatment of leukemia, comprising as an active ingredient a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  5. In Article 4, The above compound is, A pharmaceutical composition characterized by inhibiting cell proliferation of leukemia cell lines.
  6. In Article 4, The above leukemia is, A pharmaceutical composition characterized by being acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia.
  7. A food composition for preventing or improving leukemia, comprising a compound according to any one of claims 1 to 3 or a food-grade acceptable salt thereof as an active ingredient.
  8. A health functional food composition for the prevention or improvement of leukemia, comprising a compound according to any one of claims 1 to 3 or a food-grade acceptable salt thereof as an active ingredient.

Description

Novel compounds having inhibitory activity against leukemia cell lines and medical use thereof The present invention relates to a novel compound and its medical use, and more specifically, to a novel compound having inhibitory activity against leukemia cell lines and its use in treating leukemia. Leukemia is a blood cancer that occurs when normal blood cells in the bone marrow, the body's hematopoietic organ, transform into cancer cells and proliferate due to some cause. Leukemia cells proliferate indefinitely, interfering with the production of normal white blood cells, red blood cells, and platelets, thereby reducing the levels of normal blood cells and causing fatal problems in the body. Acute leukemia is a disease in which hematopoietic stem cells transform into malignant cells, proliferate in the bone marrow, spread into the peripheral blood, and then spread throughout the body, invading organs such as the liver, spleen, and lymph nodes. Acute leukemia is classified into acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) depending on the type of leukemia cells. Acute myeloid leukemia is the most common form of leukemia; it primarily affects adults, and the incidence rate increases with age. Myeloid leukemia refers to a condition in which myeloblasts account for more than 20% of the bone marrow or peripheral blood. When cancer cells grow in the bone marrow, they inhibit normal hematopoietic cells, thereby interfering with hematopoiesis. Consequently, anemia, leukopenia, thrombocytopenia, and leukocytosis occur, leading to symptoms. Among these, the acute form of myeloid leukemia is called acute myeloid leukemia. Standard treatment methods for leukemia include chemotherapy, hematopoietic stem cell transplantation, and radiation therapy; in the case of chemotherapy, the combination of two or more anticancer drugs is typically employed. Ideally, anti-leukemia drugs should exhibit a selective effect only on leukemia cells without inhibiting normal hematopoiesis or causing other harmful side effects. However, while most anti-leukemia drugs can kill leukemia cells to some extent by approaching this ideal state, they also inhibit normal hematopoiesis and cause other harmful side effects, thus limiting their effectiveness in leukemia treatment. Furthermore, in drug-resistant leukemia cells, the anti-tumor effect is weak, and there may be cases where sufficient chemotherapy cannot be administered due to potential side effects. Therefore, there is a need for a new leukemia treatment with minimal side effects and excellent therapeutic efficacy. Figure 1 shows the results of evaluating cell viability under single administration conditions in human myeloid leukemia cell line MV4-11 of representative novel compounds according to one experimental example of the present invention. Figure 2 shows the cell proliferation inhibitory activity of each novel compound in the MV4-11 cell line, and the GI 50 (Growth Inhibition 50%) value and coefficient of determination ( R² ) of each compound were confirmed. Figure 3 evaluates the cytotoxicity of the representative compound 1 (DN302319) in various leukemia cell lines (MV4-11, MOLM-13, THP-1, K562), and confirms that it does not show toxicity in normal cells but exhibits excellent selective inhibitory activity in leukemia cell lines. Figure 4 is a graph showing the experimental results of cell proliferation inhibitory activity (GI 50 , R 2 ) for four representative compounds. The present invention will be described in detail below. The inventors synthesized a novel compound and confirmed that the compound exhibits excellent inhibitory activity against leukemia cell lines, thereby effectively treating acute myeloid leukemia, and thus completed the present invention. The present invention provides a compound selected from a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: <Chemical Formula 1> In the above chemical formula 1, R1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, or amino, and R2 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, or (C1-C4)alkoxy, and R 3 is or Selected from, where R 3' is hydrogen or (C1-C4)alkyl, and X can be selected from oxygen or sulfur. Preferably, in the above formula 1, R1 is selected from (C1-C2)alkyl, trifluoromethyl, or amino, R2 is selected from hydrogen, halogen, (C1-C2)alkyl, trifluoromethyl, or (C1-C2)alkoxy, and R3 ' can be selected from hydrogen or (C1-C2)alkyl. More preferably, the compound is 3-(4-thiouredobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)-phenyl)benzamido (Compound 1), 3-(4-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 2), 4-methyl-3-(3-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 3), 4-methyl-3-(3-(3-methyluredo)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido (Compound 4), 4-methyl-3-(3-thiouredobenzamido)-N-(4-((trifluoromethyl)sulfonyl)